CN1323312A - Crystallization of doxorubicin hydrochloride - Google Patents
Crystallization of doxorubicin hydrochloride Download PDFInfo
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- CN1323312A CN1323312A CN99812230A CN99812230A CN1323312A CN 1323312 A CN1323312 A CN 1323312A CN 99812230 A CN99812230 A CN 99812230A CN 99812230 A CN99812230 A CN 99812230A CN 1323312 A CN1323312 A CN 1323312A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
A method for crystallizing doxorubicin hydrochloride from an aqueous solution thereof which comprises crystallizing under a condition comprising a temperature of 40 DEG C or higher, and an aggregate of doxorubicin hydrochloride crystals having excellent solubility particularly in water.
Description
Technical field
The present invention relates to the crystallization and the doxorubicin hydrochloride crystallization aggregation that certain characteristic is arranged of doxorubicin hydrochloride.
Background technology
Zorubicin (being called adriamycin again) can be represented by the formula,
It is the antibiotics that streptomycete (Streptomyces peuceticus var caestius) produces.In addition, Zorubicin also can provide by chemical conversion from daunorubicin (being called daunomycin again).This hydrochloride (being doxorubicin hydrochloride) has wide anticancer spectrum, and excellent usefulness is arranged in the chemotherapy of malignant lymphoma, lung cancer, digestive organ cancer, breast cancer etc.Now, the liquor of doxorubicin hydrochloride (solution of water for injection or normal saline solution) has been widely used in the clinical treatment of above-mentioned various cancers.
As such liquor raw material, existing Powdered or crystalloid doxorubicin hydrochloride provides, but present available commodity are may not necessarily be satisfactory aspect the solvability of water.Particularly, when preparing liquor when face use at the treatment scene before, providing of the solid-state doxorubicin hydrochloride that can more promptly be dissolved in the water is that people expect.
On the other hand, Powdered or crystalloid doxorubicin hydrochloride usually can be by from organic solvent system or contain the aqueous solvent system of organic solvent precipitation or partial crystallization obtains, but aspect the minimizing of residual solvent or the removal difficult point is being arranged, or the low situation of purpose crystallization yield is in the majority.
At present, as medical commercially available solid-state doxorubicin hydrochloride,, in water, during stir process, also need about 10 minutes under the temperature (25 ℃) around until dissolving although residual solvent is below allowance on its application target.And, also observe major part sometimes and also have a small amount of molten residual thing after being dissolved in the water.USP (American Pharmacopeia) standard substance as the doxorubicin hydrochloride standard (can be available from (wealth) Japanese official compendium association, Shibuya district, Tokyo Shibuya 2-12-15), solvability to water is excellent, however, can also observe little molten residual thing sometimes after dissolution process.
Disclosure of the Invention
Therefore, the purpose of this invention is to provide the crystallization that a kind of yield of following partial crystallization improves the minimizing excellence of self-evident, residual solvent and can bring the final doxorubicin hydrochloride goods that solvability is high in the water, and the doxorubicin hydrochloride crystallization aggregation that possesses such characteristic.
People such as the present invention find when the crystallization of doxorubicin hydrochloride is inquired into, with the general general knowledge of partial crystallization (with reference to opening clear 59-118797 communique or United States Patent (USP) the 4th such as the spy, 861, No. 870 specification sheetss) difference, at certain more than the certain temperature, in specific solvent system, implement partial crystallization, just can achieve the above object.
Therefore, the present invention relates to a kind of crystallization, it is characterized in that it being the crystallization of doxorubicin hydrochloride in a kind of solution that contains doxorubicin hydrochloride, wherein, the solution that contains doxorubicin hydrochloride is a kind ofly to contain the poor solvent of doxorubicin hydrochloride and the group water solution of doxorubicin hydrochloride itself, and carries out partial crystallization in the temperature more than 40 ℃.
Again, the present invention also relates to the crystallization aggregation of doxorubicin hydrochloride, it is characterized in that
(A) moisture is below 2% (weight), and other total residual solvent is below 1.5%,
(B) median size, in the round equivalent diameter of projection image, more than 15 μ m and
(C) solvability shows, in the water under 25 ℃ of agitation conditions, in about dissolving in fact fully below 2 minutes.
Invent best example
Can supply with doxorubicin hydrochloride according to crystallization of the present invention (below be also referred to as DOX.HCl), how have nothing to do with its manufacturing process or refining stage, as long as have certain certain above purity.That is, crystallization of the present invention can be used to be intended to obtain slightly the preparation refining stage and the polishing stage of being intended to obtain end article of refining DOXHCl.Yet according to crystallization of the present invention, if consider the easiness that reduces its residual solvent or can obtain effect, the effect of the crystallization etc. of high resolution in the water, the polishing stage of DOXHCl uses more fortunately.Therefore, under the guiding theory of using mainly as the polishing stage, the present invention is described below, but should be understood that and be not limited to these.
Can supply with the solution that contains DOXHCl according to crystallization of the present invention, be the group water solution that contains the poor solvent of Zorubicin (below be also referred to as DOX) and DOX.Such group water solution is at first DOXHCl to be dissolved in the water, or DOX is dissolved in dilute hydrochloric acid (for example 0.001 N HCl) aqueous solution, but different because of situation, also can contain the water miscibility organic solvent based on following poor solvent in the above-mentioned water.Secondly, preparation, that contain DOXHCl like this group water solution (to call solvent soln in the following text) mixes with the poor solvent of DOX usually.This mixing both can be group water solution and the poor solvent mixed once that contains DOXHCl, also can be that the former adds among the latter on a small quantity repeatedly, or opposite, and the latter adds among the former on a small quantity repeatedly.
As poor solvent, be can with water blended organic solvent freely, so long as can reach the purpose person of the present invention, any can, but in general, can enumerate methyl alcohol, ethanol, Virahol, acetonitrile, acetone and more than one mixed solvent in the middle of these.In the middle of these, the mixed solvent of ethanol, acetone and ethanol and acetone is preferably, and wherein good especially is the mixed solvent of ethanol, ethanol and acetone.The mixed solvent of ethanol and acetone is preferably ethanol and acetone with 4: 1～1: 1,2.5: 1 mixed person especially.
Organic solvent when on the other hand, comprising organic solvent in the above-mentioned solvent soln can be any in the above-mentioned poor solvent.Yet, being preferably ethanol is added in the water (sour water), especially good is this moment, water and alcoholic acid ratio were 7.5: 5～7.5: 15.
In such solvent system, the solvent that good especially is in the above-mentioned solvent soln by the water and the ethanol of better ratio forms, to form such solvent by the ethanol of better ratio and acetone be to make up to poor solvent.
The combination meeting of such solvent soln and poor solvent is different because of the amount of DOXHCl, but in general, the ratio of solvent soln and poor solvent is 1: 2～1: 10, is preferably about 1: 5.
Such solvent system solution that form, that contain DOXHCl gets final product so long as can make DOX.HCl be in dissolved state before the partial crystallization, and the concentration of DOXHCl is unqualified.Yet in general, the concentration of DOX.HCl should be below 10% (weight/volume), 8～4.5% (weight/volume) more fortunately.
According to the present invention, the temperature of carrying out partial crystallization must be set in more than 40 ℃.This temperature, when the group water solution that contains DOX.HCl when preparing more than 40 ℃, can remain unchanged or reduce some temperature, but usually this contains the group water solution of DOXHCl 5 ℃～35 ℃ preparations, thereby will be warmed up to 40 ℃ from these temperature and carry out partial crystallization again.Temperature more than 40 ℃, be preferably 45 ℃～75 ℃, good especially be 50～65 ℃.In addition, according to the present invention, can place the solution that contains DOXHCl under the temperature in the said temperature scope any period in partial crystallization, but be preferably, run through whole partial crystallization process, all in the said temperature scope, stir or leave standstill the group water solution that contains DOXHCl.And the partial crystallization temperature also can change in the said temperature scope, but for for the purpose of easy to operate, can be set in the temperature of constant.
The needed time of partial crystallization can be to select to obtain the purpose DOXHCl crystalline time with desired yield according to employed solvent.Yet, under above-mentioned better condition, generally more than 1 hour, 2～4 hours more fortunately, different from 2.5～5 hours because of situation, just can obtain purpose DOXHCl with high yield.
Like this, just, formed purpose DOXHCl crystallization.These crystallizations can separation from partial crystallization solution, collection, drying.
The above-mentioned crystallization that obtains according to crystallization of the present invention, be that the about 15 μ m of median size are above, and size distribution is also extremely narrow, thereby by adopting suitable strainer to filter, just can very successfully separate, collect, but be not limited to this, also can adopt its itself separation known means.
Dry means, so long as the biologic activity of DOXHCl is not produced dysgenic means, any means all can be selected for use, but in general, are preferably vacuum (decompression) desiccating method.In addition, before vacuum-drying, also can carry out air-dry at ambient temperature.Temperature when carrying out vacuum-drying can be set in 5 ℃～75 ℃, 40 ℃ more fortunately～60 ℃, and the decompression degree can be selected arbitrarily.Use measure in the HPLC method tire to the situation of the above person of about 97% (with dry-matter) as the raw material of supply partial crystallization under, the vacuum-drying time reached more than 1 hour, just can obtain the purity test (HPLC method), residual solvent test (GC method) and the qualified goods of potency test (HPLC method) that are undertaken by American Pharmacopeia (DOXHCl of USP23) specification usually.
By the DOXHCl crystallization that obtains according to crystallization of the present invention, under the decompression such as 5～10mmHg, carry out can obtaining the crystallization aggregation that crystallization totally has following characteristic under 4 hours vacuum drying situations at 40 ℃:
(A) moisture is below 2% (weight), and other total residual solvent is below 1.5%,
(B) median size, in the round equivalent diameter of projection image, more than 15 μ m and
(C) solvability shows, in the water under 25 ℃ of agitation conditions,, be noted that in about dissolving in fact fully below 2 minutes, " crystallization aggregation " described in the present invention is not to refer to the thing of each crystallization by specific cohesions such as physical bond power, and only refers to each crystalline group.
Such crystallization aggregation, with compare with the above-mentioned commercially available product that can be used as headed by the DOXHCl crystallization aggregation that the USP standard product buy from (wealth) Japanese official compendium association, on the remarkable high this point of solvability, be the novel crystallization aggregation that can clearly be different from known DOXHCl.
Therefore, described crystallization aggregation also is a kind of form of the present invention.Under using ethanol and the situation of acetone as the poor solvent in the crystallization of the present invention, the described crystallization aggregation that can provide is that moisture content is about below 1% in the per unit crystallization aggregation gross weight, acetone is about below 0.4%, and ethanol is about below 1.0%, and such crystallization aggregation is a better form of the present invention.
According to crystallization aggregation of the present invention, all described solvabilities all are better forms 1.5～2 minutes or its following person.
In addition,, it is characterized in that according to DOXHCl crystallization of the present invention group, roughly the same or lower when no matter water absorbability is compared with the USP standard product, all demonstrate aforesaid good solubility.
Therefore, according to the present invention, the novel crystallization and the crystallization aggregation that can obtain being suitable for providing the DOXHCl crystallization aggregation of DOXHCl liquor are disclosed.
Below be described more specifically the present invention with specific examples, but these examples only are easily purpose so that the understanding of the present invention becomes, and there is no the intention that makes the present invention be defined in these examples.
The measuring method of various characteristics described in the present invention:
＜dissolubility test 〉
In the beaker of 20ml (internal diameter 30mm), add 5ml water, add water 50mg DOXHCl crystallization sample again, 25 ℃ with magnetic stir bar (diameter 6mm * length 10mm), stir samples with about 600 rev/mins.The dissolved state that detected by an unaided eye one time in per 30 seconds was measured simultaneously until the consoluet time.
The mensuration of＜residual solvent 〉
A) moisture determination: sample 10～15mg, with flat natural pond industry corporate system AQ-6 type determination of trace water device, carry out according to coulometric titration.During mensuration, use HYDRANAL-Coulomat AK/ ketone to use (the pure pharmaceutical worker's industry of woods company) in the generation liquid, and to using HYDRANAL-Coulomat CG-K/ ketone to use (the pure pharmaceutical worker's industry of woods company) in the utmost point liquid.
B) poor solvent is measured: with following vapor-phase chromatography (head space method).Gas chromatograph GC-14A (being equipped with hydrogen flameionization comparator (FID)) (Shimadzu Seisakusho Ltd.'s system) goes up J ﹠amp is installed; W corporate system DB-WAX post under the condition of the about 1.0ml/ of use traffic minute helium, with head space method analytical sample, is calculated the amount of poor solvent in the sample.
＜water absorbability 〉
With following agar diffusion method.Specifically, water absorbability is to add the about 15～20mg of sample in the cylindric cup of diameter 6mm, degree of depth 6mm, and (placed 15 minutes for 50～60%RH) time, mensuration changes in weight is at this moment estimated in certain temperature (25 ℃) and relative humidity.
Be noted that the metewand of employing is in following each example: weight increase is 0.40% above person, water absorbability big (-); More than 0.20%～0.40% following person, in the water absorbability (±); 0.20% following person, water absorbability little (+).
＜median size 〉
Median size adopts microscopy shown below (projection image), represents to have with particle shadow area circular diameter of the same area, promptly with so-called Heywood diameter (circle equivalent diameter) expression.
Method: small amount of crystalline is placed on the slide glass, adds 1～2 lipophilic surfactant (sesquialter oleic acid sorbitan ester) and make it to disperse, with polarizing microscope (3.3 times of phtographic lenses are to 20 times of the composition lens) photography that is equipped with camera.On photo, select 10 of representational any crystallizations, measure its major diameter and minor axis.Calculate crystalline (projection) area with major diameter * minor axis, with circular diameter of the same area therewith as particle diameter.
Example 1～59: partial crystallization and crystalline are collected
The DOXHCl of predetermined amount (tire: about 960～980 μ g/mg) add to and added in case of necessity in dissolution solvent 0.001N hydrochloric acid, that put down in writing in the following table I system, at room temperature filter with absorbent cotton then by (about 25 ℃) dissolving.Filtrate is with poor solvent, rise to preset temperature after, stir about 1 hour (200rpm).The crystallization that leaching is separated out is after poor solvent 10ml washing, 40 ℃, vacuum (5～10mmHg) times dried overnight.
(molten → poor: solvent soln adds in the poor solvent for ratio of mixture (volume ratio) under the DOXHCl amount of using in each example, quantity of solvent, the mixed solvent situation, solvent addition means; Poor → molten: poor solvent adds in the solvent soln; Poor → molten/numerical value min and molten → poor/numerical value min refer to respectively poor solvent and solvent soln this numerical value time (minute) in on a small quantity repeatedly mode add), the partial crystallization temperature (℃), stirring velocity (rpm), yield (%), water ratio (%), the containing ratio (%) of each poor solvent, median size (μ m) during partial crystallization be summarised in respectively in following table I～II.A is that acetone, E are ethanol in the table, and AN is an acetonitrile, and IP is a Virahol.The partial crystallization temperature is 25 → 60, means from 25 ℃ to be warmed up to 60 ℃ (about 3.5 ℃/minute).Blank column in the table does not mean and measures.In the table II, moisture (%), A (%) and E (%) represent residual solvent respectively, promptly represent water ratio and poor solvent containing ratio.At the poor solvent containing ratio is under the situation of acetonitrile and Virahol, is marked especially.Table I: partial crystallization condition
Table I: partial crystallization condition (continuing)
Table I: partial crystallization condition (continuing)
Table II: partial crystallization and dried result
Table II: partial crystallization and dried result (continuing)
Table II: partial crystallization and dried result (continuing)
*AN: acetonitrile
*IP: Virahol
| Example | DOX (mg) | Dissolution solvent | Poor solvent | Addition means | The partial crystallization temperature |
| ????1 | ?499.4 | Water (12.5ml) | A(250ml) | Molten → poor | ????0 |
| ????2 | ?497.4 | Sour water (12.5ml) | A(250ml) | Molten → poor | ????0 |
| ????3 | ?505.2 | Sour water (12.5ml) | A(250ml) | Poor → molten | ????0 |
| ????4 | ?508.6 | Sour water (12.5ml) | A(250ml) | Poor → molten | ????25 |
| ????5 | ?500 | Sour water (12.5ml) | A/E(2∶1)(125ml) | Poor → molten | ????5 |
| ????6 | ?500 | Sour water (12.5ml) | A/E(3∶1)(125ml) | Poor → molten | ????5 |
| ????7 | ?500 | Sour water (12.5ml) | A/E(4∶1)(125ml) | Poor → molten | ????5 |
| ????8 | ?1003 | Sour water (12.5ml) | A/E(4∶1)(125ml) | Poor → molten | ????5 |
| ????9 | ?1000.1 | Sour water (1: 1) (25ml) | A/E(4∶1)(112.5ml) | Poor → molten | ????5 |
| ????10 | ?498.6 | Sour water (12.5ml) | A/E(2∶1)(125ml) | Poor → molten | ????25 |
| ????11 | ?501.6 | Sour water (12.5ml) | A/E(3∶1)(125ml) | Poor → molten | ????25 |
| ????12 | ?504.8 | Sour water (12.5ml) | A/E(4∶1)(125ml) | Poor → molten | ????25 |
| ????13 | ?1003 | Sour water/E (1: 1) (25ml) | A/E(1∶2)(112.5ml) | Poor → molten | ????25 |
| ????14 | ?1002.3 | Sour water/E (1: 1) (25ml) | A/E(1∶1)(112.5ml) | Poor → molten | ????25 |
| ????15 | ?1003.4 | Sour water/E (1: 1) (25ml) | A/E(3∶2)(112.5ml) | Poor → molten | ????25 |
| ????16 | ?1001.1 | Sour water (12.5ml) | A/E(2∶1)(125ml) | Poor → molten | ????25 |
| ????17 | ?1000.7 | Sour water (12.5ml) | A/E(3∶1)(125ml) | Poor → molten | ????25 |
| ????18 | ?1001.3 | Sour water (12.5ml) | A/E(4∶1)(125ml) | Poor → molten | ????25 |
| ????19 | ?1002.8 | Sour water/E (1: 1) (25ml) | A/E(1∶2)(112.5ml) | Poor → molten | ????40 |
| ????20 | ?1002.9 | Sour water/E (1: 1) (25ml) | A/E(2∶1)(112.5ml) | Poor → molten | ????40 |
| ????21 | ?1003.5 | Sour water/E (1: 1) (25ml) | A/E(1∶2.3)(112.5ml) | Poor → molten | ????60 |
| Example | DOX (mg) | Dissolution solvent | Poor solvent | Addition means | The partial crystallization temperature |
| ?22 | ?1001.5 | Sour water/E (1: 1) (25ml) | A/E(1∶1.2)(112.5ml) | Poor → molten | ????60 |
| ?23 | ?1005.1 | Sour water/E (1: 1) (25ml) | E(112.5ml) | Molten → poor | ????60 |
| ?24 | ?1001.2 | Sour water/E (1: 1) (25ml) | E(112.5ml) | Poor → molten | ????60 |
| ?25 | ?1001.5 | Sour water/E (1: 1) (25ml) | A/E(1∶1.2)(112.5ml) | Poor → molten/100rpm | ????60 |
| ?26 | ?1006.4 | Sour water/E (1: 1) (25ml) | A/E(1∶1.2)(112.5ml) | Poor → molten/200rpm | ????60 |
| ?27 | ?1003.9 | Sour water/E (1: 1) (25ml) | A/E(1∶1.2)(112.5ml) | Poor → molten/300rpm | ????60 |
| ?28 | ?1002.2 | Sour water/E (1: 1) (25ml) | A/E(1∶3)(112.5ml) | Molten → poor | ????60 |
| ?29 | ?1000.7 | Sour water/E (1: 1) (25ml) | A/E(1∶2)(112.5ml) | Molten → poor | ????60 |
| ?30 | ?1003.6 | Sour water/E (1: 1) (25ml) | A/E(1∶1)(112.5ml) | Molten → poor | ????60 |
| ?31 | ?1001.4 | Sour water/E (1: 1) (25ml) | A/E(2∶1)(112.5ml) | Molten → poor | ????60 |
| ?32 | ?1003 | Sour water/E (1: 1) (25ml) | A/E(3∶1)(112.5ml) | Molten → poor | ????60 |
| ?33 | ?1001.1 | Sour water/E (1: 1) (25ml) | A/E(1∶2)(112.5ml) | Poor → molten/200rpm | ????25→60 |
| ?34 | ?1000.9 | Sour water/E (1: 1) (25ml) | A/E(1∶1)(112.5ml) | Poor → molten/200rpm | ????25→60 |
| ?35 | ?1000.4 | Sour water/E (1: 1) (25ml) | A/E(2∶1)(112.5ml) | Poor → molten/200rpm | ????25→60 |
| ?36 | ?1001.3 | Sour water/E (1: 1) (25ml) | A/E(1∶1)(112.5ml) | Poor → molten/100rpm | ????25→60 |
| ?37 | ?1000.7 | Sour water/E (1: 1) (25ml) | A/E(1∶2)(112.5ml) | Molten → poor/200rpm | ????60 |
| ?38 | ?1001.9 | Sour water/E (2: 3) (25ml) | A/E(1∶2.36)(125ml) | Molten → poor/200rpm | ????60 |
| ?39 | ?1001.5 | Sour water/E (3: 7) (25ml) | A/E(1∶2.42)(125ml) | Molten → poor/200rpm | ????60 |
| ?40 | ?1001.4 | Sour water/E (3: 7) (25ml) | A/E(1∶3.58)(125ml) | Molten → poor/200rpm | ????60 |
| ?41 | ?1001.5 | Sour water/E (3: 7) (25ml) | A/E(1∶2.42)(125ml) | Molten → poor/200rpm | ????60 |
| ?42 | ?1000.3 | Sour water/E (3: 7) (25ml) | A/E(1∶1.28)(125ml) | Molten → poor/200rpm | ????60 |
| Example | DOX (mg) | Dissolution solvent | Poor solvent | Addition means | The partial crystallization temperature |
| ?43 | ?2000(g) | Sour water/E (2: 3) (501) | A/E(1∶3)(2501) | Molten → poor | ????65 |
| ?44 | ?1001.1 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/5min | ????60 |
| ?45 | ?1002.6 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/30min | ????60 |
| ?46 | ?1005.4 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/60min | ????60 |
| ?47 | ?1002.7 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/60min | ????40 |
| ?48 | ?999.7 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/60min | ????45 |
| ?49 | ?1004.6 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/60min | ????50 |
| ?50 | ?1000.2 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/60min | ????55 |
| ?51 | ?1000.2 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/60min | ????60 |
| ?52 | ?995.7 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/60min | ????70 |
| ?53 | ?997.3 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/3hr | ????60 |
| ?54 | ?1001.4 | Sour water/E (3: 7) (25ml) | A/E(1∶3.56)(125ml) | Molten → poor/1+2hr | ????60→25 |
| ?55 | ?999.3 | Sour water/E (2: 3) (25ml) | A/E(1∶3)(125ml) | Molten → poor | ????60 |
| ?56 | ?1000.6 | Sour water/AN (2: 3) (25ml) | A/AN(1∶3)(125ml) | Molten → poor | ????60 |
| ?57 | ?1000.1 | Sour water/IP (2: 3) (25ml) | A/IP(1∶3)(125ml) | Molten → poor | ????60 |
| ?58 | ?999.8 | Sour water/AN (2: 3) (25ml) | A/AN(1∶3)(125ml) | Molten → poor | ????25 |
| ?59 | ?999.8 | Sour water/IP (2: 3) (25ml) | A/IP(1∶3)(125ml) | Molten → poor | ????25 |
| Example | Yield (%) | Moisture (%) | ????A ????(％) | ????E ????(％) | Water absorbability | Median size (μ m) |
| ????1 | ????81.6 | ????0.77 | ????0.54 | ????- | ||
| ????2 | ????78.4 | ????1.05 | ????0.58 | ????- | ????＜4 | |
| ????3 | ????72.5 | ????0.82 | ????0.92 | ????- | ||
| ????4 | ????86 | ????0.53 | ????1.09 | ????- | ????＜4 | |
| ????5 | Can not reclaim | |||||
| ????6 | Can not reclaim | |||||
| ????7 | Can not reclaim | |||||
| ????8 | ????62.7 | ????0.67 | ????0.55 | ????0.34 | ????- | |
| ????9 | ????78.1 | ????0.79 | ????0.53 | ????0.19 | ????- | |
| ????10 | Can not reclaim | |||||
| ????11 | Can not reclaim | |||||
| ????12 | Can not reclaim | |||||
| ????13 | ????62.3 | ????1 | ????0.36 | ????0.55 | ????± | ????＜4 |
| ????14 | ????74.7 | ????0.55 | ????0.48 | ????0.43 | ????± | |
| ????15 | ????70.2 | ????0.57 | ????0.55 | ????0.41 | ????- | |
| ????16 | ????70.9 | ????0.7 | ????0.69 | ????0.36 | ????± | ????＜4 |
| ????17 | ????63.1 | ????0.62 | ????0.78 | ????0.3 | ????- | |
| ????18 | ????63.6 | ????0.55 | ????0.86 | ????0.26 | ????- | |
| ????19 | ????63.6 | ????0.59 | ????0.35 | ????0.59 | ????± | ????17 |
| ????20 | ????73 | ????0.73 | ????0.69 | ????0.4 | ????+ | ????7 |
| ????21 | ????69.2 | ????0.26 | ????0.22 | ????0.5 | ????+ | ????54 |
| Example | Yield (%) | Moisture (%) | ????A ????(％) | ????E ????(％) | Water absorbability | Median size (μ m) |
| ?22 | ????67.6 | ????0.32 | ????0.34 | ????0.46 | ????+ | ????47 |
| ?23 | ????56.3 | ????0.21 | ????0.78 | ????± | ????39 | |
| ?24 | ????55.1 | ????0.1 | ????0.71 | ????+ | ????51 | |
| ?25 | ????67.6 | ????0.32 | ????0.34 | ????0.46 | ????+ | |
| ?26 | ????71.5 | ????0.31 | ????0.37 | ????0.41 | ????+ | |
| ?27 | ????65.7 | ????0.01 | ????0.37 | ????0.4 | ????± | |
| ?28 | ????57.2 | ????0.4 | ????0.26 | ????0.64 | ????+ | ????37 |
| ?29 | ????69.5 | ????0.06 | ????0.37 | ????0.65 | ????+ | |
| ?30 | ????81.7 | ????0.26 | ????0.55 | ????0.57 | ????+ | ????39 |
| ?31 | ????78.5 | ????0.12 | ????0.72 | ????0.43 | ????+ | |
| ?32 | ????78.8 | ????0.32 | ????0.71 | ????0.3 | ????+ | ????34 |
| ?33 | ????65.3 | ????0.13 | ????0.33 | ????0.59 | ????± ?????? | ????25 |
| ?34 | ????68.8 | ????0.27 | ????0.47 | ????0.49 | ????± | ????23 |
| ?35 | ????93.6 | ????0.23 | ????0.82 | ????0.48 | ????± | ????20 |
| ?36 | ????64.6 | ????0.11 | ????0.46 | ????0.47 | ????± | |
| ?37 | ????69.5 | ????0.06 | ????0.37 | ????0.65 | ????+ | |
| ?38 | ????71 | ????0.36 | ????0.35 | ????0.66 | ????+ | ????28 |
| ?39 | ????79.6 | ????0.36 | ????0.4 | ????0.76 | ????+ | |
| ?40 | ????74.1 | ????0.18 | ????0.27 | ????0.67 | ????± | ????18 |
| ?41 | ????79.6 | ????0.36 | ????0.4 | ????0.76 | ????+ | |
| ?42 | ????80.8 | ????0.3 | ????0.57 | ????0.66 | ????+ | ????34 |
| Example | Yield (%) | Moisture (%) | ????A ????(％) | ????E ????(％) | Water absorbability | Median size (μ m) |
| ?43 | ????70.3 | ????0.09 | ????0.16 | ????0.37 | ????+ | |
| ?44 | ????84.4 | ????0.38 | ????0.29 | ????0.69 | ????+ | ????28 |
| ?45 | ????84.3 | ????0.64 | ????0.26 | ????0.66 | ????+ | ????46 |
| ?46 | ????78.1 | ????0.21 | ????0.12 | ????0.67 | ????+ | ????86 |
| ?47 | ????86.8 | ????0.19 | ????0.43 | ????0.96 | ????± | ????60 |
| ?48 | ????81.3 | ????0.1 | ????0.3 | ????0.84 | ????+ | ????89 |
| ?49 | ????84.5 | ????0.44 | ????0.29 | ????0.81 | ????+ | ????71 |
| ?50 | ????77.5 | ????0.79 | ????0.32 | ????0.73 | ????+ | |
| ?51 | ????76 | ????0.08 | ????0.25 | ????0.61 | ????+ | ????73 |
| ?52 | ????81.1 | ????0.09 | ????0.19 | ????0.49 | ????+ | |
| ?53 | ????84.1 | ????0 | ????0.25 | ????0.59 | ????+ | |
| ?54 | ????83.4 | ????1.01 | ????0.2 | ????0.5 | ????+ | |
| ?55 | ????75.7 | ????1.06 | ????0.27 | ????0.73 | ????+ | ????24 |
| ?56 | ????86.4 | ????0.98 | ????0.21 | ????0.68 * | ????+ | ????37 |
| ?57 | ????82.3 | ????0.15 | ????0.39 | ????0.72 ** | ????± | ????35 |
| ?58 | ????88.8 | ????0.72 | ????0.21 | ????0.58 * | ????- | ????＜4 |
| ?59 | ????88.1 | ????0.05 | ????0.51 | ????1.00 ** | ????- | ????＜4 |
Be noted that in the above-mentioned example that example 1～18,58 and 59 is comparative examples, example 19～57th, embodiments of the invention.＜dissolubility test 〉
As a comparison DXRUSP standard substance (LotJ) (median size 28 μ m) and example 2,46,51,55,56,57 and 58 are carried out above-mentioned dissolubility test, and it the results are summarized in the table III.
Table III: solvability sample dissolution time (branch) DXR-USP (comparison) 3～3.5 in the water
*
Example 2 4～4.5
Example 46 1.5～2
Example 51 1.5～2
Example 55 1.5～2
Example 56 1.5～2
Example 57 1.5～2
Example 58 14.5～15
*Most of dissolving, but observe micro-molten residual thing.
The possibility of utilizing on the industry
According to crystallization of the present invention, can obtain expeditiously having the ADMh crystallization of the characteristic of excellence when preparing with raw material than the USP standard product as liquor, especially these crystallizations have the remarkable high feature of dissolving in water. Therefore, the present invention can be used for the pharmaceuticals manufacturing industry.
Claims (7)
1. crystallization, it is characterized in that it being the crystallization of doxorubicin hydrochloride in a kind of solution that contains doxorubicin hydrochloride, wherein, the solution that contains doxorubicin hydrochloride is a kind ofly to contain the poor solvent of doxorubicin hydrochloride and the group water solution of doxorubicin hydrochloride itself, and carries out partial crystallization in the temperature more than 40 ℃.
2. the crystallization of claim 1 record, wherein, poor solvent is any or mixture more than 2 kinds of selecting one group that forms from methyl alcohol, ethanol, Virahol, acetonitrile and acetone.
3. the crystallization of claim 1 record, wherein, poor solvent is a kind of or mixture in ethanol and the acetone.
4. the crystallization of any one record in the claim 1～3, wherein, the ratio of water and poor solvent is 1: 2～1: 10 in the described group water solution.
5. the crystallization of any one record in the claim 1～4, wherein, partial crystallization carries out at 45 ℃～75 ℃.
6. the crystallization of any one record in the claim 1～5 wherein, has carried out the doxorubicin hydrochloride crystallization aggregation of drying treatment behind the partial crystallization
(A) other following residual solvent of the following moisture and 1.5% (weight) of 2% (weight) is arranged,
(B) in the round equivalent diameter of projection image, have the above median size of 15 μ m and
(C) in the water under 25 ℃ of agitation conditions, have in about consoluet in fact solvability below 2 minutes.
7. the crystallization aggregation of doxorubicin hydrochloride is characterized in that
(A) moisture is below 2% (weight), and other total residual solvent is below 1.5%,
(B) median size, in the round equivalent diameter of projection image, more than 15 μ m and
(C) solvability shows, in the water under 25 ℃ of agitation conditions, in about dissolving in fact fully below 2 minutes.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP309542/1998 | 1998-10-16 | ||
| JP30954298 | 1998-10-16 |
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| CN1323312A true CN1323312A (en) | 2001-11-21 |
| CN1188424C CN1188424C (en) | 2005-02-09 |
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| CNB998122300A Expired - Lifetime CN1188424C (en) | 1998-10-16 | 1999-10-15 | Crystallization of doxorubicin hydrochloride |
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| US (1) | US6653455B1 (en) |
| EP (1) | EP1122260B1 (en) |
| JP (1) | JP4533537B2 (en) |
| CN (1) | CN1188424C (en) |
| AT (1) | ATE284893T1 (en) |
| AU (1) | AU750738B2 (en) |
| CA (1) | CA2347515C (en) |
| DE (1) | DE69922681T2 (en) |
| ES (1) | ES2235518T3 (en) |
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| US7388083B2 (en) * | 2005-03-07 | 2008-06-17 | Solux Corporation | Epimerization of 4′-C bond and modification of 14-CH3-(CO)-fragment in anthracyclin antibiotics |
| RU2450013C2 (en) * | 2005-12-13 | 2012-05-10 | Солюкс Корпорейшен | Method of producing 4-demethyldaunorubicin |
| US8802830B2 (en) * | 2005-12-20 | 2014-08-12 | Solux Corporation | Synthesis of epirubicin from 13-dihydrodaunorubicine |
| JP5075130B2 (en) * | 2006-01-24 | 2012-11-14 | バイオコンパティブルズ ユーケー リミテッド | Method of loading polymer particles with a drug |
| US7470672B2 (en) * | 2006-07-31 | 2008-12-30 | Savvipharm Inc. | Compositions and methods of reducing tissue levels of drugs when given as orotate derivatives |
| US7750018B2 (en) * | 2006-12-06 | 2010-07-06 | Tactical Therapeutics, Inc | Use of carboxiamidotriazole (CAI) orotate in macular degeneration |
| US8357785B2 (en) * | 2008-01-08 | 2013-01-22 | Solux Corporation | Method of aralkylation of 4′-hydroxyl group of anthracylins |
| US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
| PA8855701A1 (en) | 2008-12-23 | 2010-07-27 | NUCLEOSID ANALOGS | |
| WO2010075554A1 (en) | 2008-12-23 | 2010-07-01 | Pharmasset, Inc. | Synthesis of purine nucleosides |
| JP5713919B2 (en) | 2008-12-23 | 2015-05-07 | ギリアド ファーマセット エルエルシー | Nucleoside phosphoramidate |
| TWI598358B (en) | 2009-05-20 | 2017-09-11 | 基利法瑪席特有限責任公司 | Nucleoside phosphoramidates |
| EP2301943B1 (en) * | 2009-09-08 | 2014-01-08 | Heraeus Precious Metals GmbH & Co. KG | Crystallization of epidaunorubicin x HCI |
| PL3290428T3 (en) | 2010-03-31 | 2022-02-07 | Gilead Pharmasset Llc | Tablet comprising crystalline (s)-isopropyl 2-(((s)-(((2r,3r,4r,5r)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2h)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate |
| JP5872539B2 (en) | 2010-03-31 | 2016-03-01 | ギリアド ファーマセット エルエルシー | Purine nucleoside phosphoramidate |
| EP2752422B1 (en) | 2010-03-31 | 2017-08-16 | Gilead Pharmasset LLC | Stereoselective synthesis of phosphorus containing actives |
| TW201242974A (en) | 2010-11-30 | 2012-11-01 | Gilead Pharmasset Llc | Compounds |
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| YU33730B (en) * | 1967-04-18 | 1978-02-28 | Farmaceutici Italia | Process for preparing a novel antibiotic substance and salts thereof |
| US3803124A (en) * | 1968-04-12 | 1974-04-09 | Farmaceutici It Soc | Process for the preparation of adriamycin and adriamycinone and adriamycin derivatives |
| GB1457632A (en) * | 1974-03-22 | 1976-12-08 | Farmaceutici Italia | Adriamycins |
| IT1155446B (en) | 1982-12-23 | 1987-01-28 | Erba Farmitalia | PROCEDURE FOR THE PURIFICATION OF ANTHRACYCLINONIC GLUCOSIDES BY SELECTIVE ADSOBMENT ON RESINS |
| HU204570B (en) | 1989-09-04 | 1992-01-28 | Gyogyszerkutato Intezet | Process for purifying adriamycin-hydrochloride |
| JP3980101B2 (en) * | 1996-11-25 | 2007-09-26 | 財団法人微生物化学研究会 | Crystalline anthracycline antibiotic and method for producing the same |
| JP2975018B2 (en) * | 1997-11-28 | 1999-11-10 | 住友製薬株式会社 | Amrubicin hydrochloride |
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| CA2347515C (en) | 2009-10-13 |
| DE69922681T2 (en) | 2005-05-25 |
| EP1122260A1 (en) | 2001-08-08 |
| EP1122260B1 (en) | 2004-12-15 |
| CA2347515A1 (en) | 2000-04-27 |
| DE69922681D1 (en) | 2005-01-20 |
| WO2000023453A1 (en) | 2000-04-27 |
| JP4533537B2 (en) | 2010-09-01 |
| AU750738B2 (en) | 2002-07-25 |
| EP1122260A4 (en) | 2001-12-19 |
| NZ511093A (en) | 2003-04-29 |
| AU6123499A (en) | 2000-05-08 |
| US6653455B1 (en) | 2003-11-25 |
| CN1188424C (en) | 2005-02-09 |
| ATE284893T1 (en) | 2005-01-15 |
| ES2235518T3 (en) | 2005-07-01 |
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